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91.
Loftus B Anderson I Davies R Alsmark UC Samuelson J Amedeo P Roncaglia P Berriman M Hirt RP Mann BJ Nozaki T Suh B Pop M Duchene M Ackers J Tannich E Leippe M Hofer M Bruchhaus I Willhoeft U Bhattacharya A Chillingworth T Churcher C Hance Z Harris B Harris D Jagels K Moule S Mungall K Ormond D Squares R Whitehead S Quail MA Rabbinowitsch E Norbertczak H Price C Wang Z Guillén N Gilchrist C Stroup SE Bhattacharya S Lohia A Foster PG Sicheritz-Ponten T Weber C Singh U Mukherjee C El-Sayed NM 《Nature》2005,433(7028):865-868
Entamoeba histolytica is an intestinal parasite and the causative agent of amoebiasis, which is a significant source of morbidity and mortality in developing countries. Here we present the genome of E. histolytica, which reveals a variety of metabolic adaptations shared with two other amitochondrial protist pathogens: Giardia lamblia and Trichomonas vaginalis. These adaptations include reduction or elimination of most mitochondrial metabolic pathways and the use of oxidative stress enzymes generally associated with anaerobic prokaryotes. Phylogenomic analysis identifies evidence for lateral gene transfer of bacterial genes into the E. histolytica genome, the effects of which centre on expanding aspects of E. histolytica's metabolic repertoire. The presence of these genes and the potential for novel metabolic pathways in E. histolytica may allow for the development of new chemotherapeutic agents. The genome encodes a large number of novel receptor kinases and contains expansions of a variety of gene families, including those associated with virulence. Additional genome features include an abundance of tandemly repeated transfer-RNA-containing arrays, which may have a structural function in the genome. Analysis of the genome provides new insights into the workings and genome evolution of a major human pathogen. 相似文献
92.
Men and women in Great Britain are increasingly involved in a variety of economic and social roles, particularly during their mid-life period. This article examines the changes in role occupancy across four birth cohorts passing throughout mid-life over the period 1985-2000. Data from the General Household Survey is used to investigate the occupancy of four key roles: 'partner', 'parent', 'carer' and 'paid worker', analyzing separate and multiple role occupancies and level of commitment to a particular role. The implications of the findings for health and employment policies is also discussed. 相似文献
93.
Van Eerdewegh P Little RD Dupuis J Del Mastro RG Falls K Simon J Torrey D Pandit S McKenny J Braunschweiger K Walsh A Liu Z Hayward B Folz C Manning SP Bawa A Saracino L Thackston M Benchekroun Y Capparell N Wang M Adair R Feng Y Dubois J FitzGerald MG Huang H Gibson R Allen KM Pedan A Danzig MR Umland SP Egan RW Cuss FM Rorke S Clough JB Holloway JW Holgate ST Keith TP 《Nature》2002,418(6896):426-430
Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease. 相似文献
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95.
Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T-cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression. In the practice of antigen-specific immunotherapy, allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure. Although these findings indicate that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (T(reg) cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity in mice. After resolution of the inflammatory response, activated T(reg) cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, T(reg) cells function to confer 'regulatory memory' to the target tissue. These findings provide a framework for understanding how T(reg) cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity. 相似文献
96.
Ressler KJ Mercer KB Bradley B Jovanovic T Mahan A Kerley K Norrholm SD Kilaru V Smith AK Myers AJ Ramirez M Engel A Hammack SE Toufexis D Braas KM Binder EB May V 《Nature》2011,470(7335):492-497
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD. 相似文献
97.
98.
Karen Forbes Laura Skinner John D. Aplin Melissa Westwood 《Cellular and molecular life sciences : CMLS》2012,69(23):4029-4040
Insulin-like growth factors (IGFs) influence placental cell (cytotrophoblast) kinetics. We recently reported that the protein tyrosine phosphatase (PTP) SHP-2 positively regulates IGF actions in the placenta. In other systems, the closely related PTP, SHP-1, functions as a negative regulator of signaling events but its role in the placenta is still unknown. We examined the hypothesis that SHP-1 negatively regulates IGF actions in the human placenta. Immunohistochemical (IHC) analysis demonstrated that SHP-1 is abundant in cytotrophoblast. SHP-1 expression was decreased in first-trimester placental explants using siRNA; knockdown did not alter IGF-induced proliferation but it significantly enhanced proliferation in serum-free conditions, revealing that placental growth is endogenously regulated. Candidate regulators were determined by using antibody arrays, Western blotting, and IHC to examine the activation status of multiple receptor tyrosine kinases (RTKs) in SHP-1-depleted explants; amongst the alterations observed was enhanced activation of EGFR, suggesting that SHP-1 may interact with EGFR to inhibit proliferation. The EGFR tyrosine kinase inhibitor PD153035 reversed the elevated proliferation seen in the absence of SHP-1. This study demonstrates a role for SHP-1 in human trophoblast turnover and establishes SHP-1 as a negative regulator of EGFR activation. Targeting placental SHP-1 expression may provide therapeutic benefits in common pregnancy conditions with abnormal trophoblast proliferation. 相似文献
99.
Karen Lyn Bauer 《西北部美国博物学家》2011,51(3)
Cicindela arenicola Rumpp is being considered for threatened and endangered status by the U.S. Fish and Wildlife Service. Little is known about the developmental biology of this species. Adults of C. arenicola were active from April through late June and late August through early November, but generally they were not on the surface when temperatures were below 19 C or above 45 C, or when conditions were windy, cloudy, or rainy. Mating and egg-laying occurred only during the spring. Five size classes (1-,2-,3-,4-, and 5-mm diameters) of larval burrow openings were observed. Burrows of 5 mm had a mean depth of 42.23 ± 8.81 cm (1 S.D.). Larvae of C. arenicola were active from April through June and late September through mid-November. Developmental times and larval size were affected by food supplementation. Nearly all food-supplemented, 1-mm, first instars molted to larger second instars of3-mm diameter. Most nonsupplemented larvae spent several months as 2-mm second instars before growing to 3 mm in diameter. Food-supplemented larvae reached the third instar in approximately 13 months, while nonsupplemented larvae took slightly over two years to reach this stage. Development from egg to adult was estimated at two years for food-supplemented larvae and three and one-half to four years for nonsupplemented larvae. Cattle had a significant effect on larval mortality. A high percentage (76-80%) of larval C. arenicola that were stepped on by cattle never reopened their burrows. Only 14% of undisturbed larvae never reopened their burrows. Approximately 15% of 150 larvae marked in 1988 reopened burrows in 1989. 相似文献
100.
Junhua Zhao Albino Bacolla Guliang Wang Karen M. Vasquez 《Cellular and molecular life sciences : CMLS》2010,67(1):43-62
Repetitive DNA motifs are abundant in the genomes of various species and have the capacity to adopt non-canonical (i.e., non-B)
DNA structures. Several non-B DNA structures, including cruciforms, slipped structures, triplexes, G-quadruplexes, and Z-DNA,
have been shown to cause mutations, such as deletions, expansions, and translocations in both prokaryotes and eukaryotes.
Their distributions in genomes are not random and often co-localize with sites of chromosomal breakage associated with genetic
diseases. Current genome-wide sequence analyses suggest that the genomic instabilities induced by non-B DNA structure-forming
sequences not only result in predisposition to disease, but also contribute to rapid evolutionary changes, particularly in
genes associated with development and regulatory functions. In this review, we describe the occurrence of non-B DNA-forming
sequences in various species, the classes of genes enriched in non-B DNA-forming sequences, and recent mechanistic studies
on DNA structure-induced genomic instability to highlight their importance in genomes. 相似文献